The loss of tumor suppressor gene function and/or activation of proto-oncogenes through genetic or epigenetic alterations lead to the dysfunction of associated signaling pathways that control the cell cycle, progression, and proliferation. Ultimately, the gene dosage imbalance and genomic instability resulting from the clonal derivation of pre-neoplastic cells with uncontrolled programmed cell death and proliferation is associated with the development of neoplasms in both rodents and humans. We have observed that C57BL/6-Trp53 and B6C3F1-Trp53 haploinsufficient mice are more susceptible (time to tumor and prevalence) to genotoxic carcinogen or ionizing radiation induced loss of heterozygosity (LOH) and genomic instability in hematopoietic stem cell (HSC) neoplasms. 129B6F1 or C3B6F1 N12 Trp53 haploinsufficient mice develop HSC neoplasms after exposure to a variety of human carcinogens (including ionizing radiation, benzene, cyclophosphamide, melphalan, etc.) very rapidly (~2-3x faster) and with greater prevalence (60-100%) than B6129N5 Trp53 wild type mice and prevalence (with a high degree of penetrance) in B6129-Trp53+/- N5 < N12 isotype. These carcinogen induced HSC neoplasms have an increased prevalence for loss of heterozygosity involving the Trp53 locus on chromosome 11. In addition, the carcinogen specific induced pattern of LOH is consistent with either non-dysjunction or illegitimate recombination. Studies performed to date have lacked complete heterozygosity (different alleles at each genetic locus), which has prevented accurate mapping of sites of LOH associated with loss of tumor suppressor gene functions. To increase heterozygosity at all genetic loci required to determine the sites of LOH (chromosome and genome wide) we have made a series of intercrosses using mouse strains with varying susceptibility to HSC neoplasms (129 x B6, C3H x B6, and B6 x D2). Each of these strains shows varying susceptibility (penetrance) to carcinogen induced HSC neoplasm induction. Using F1 hybrids we are investigating the loss of tumor suppressor gene loci, the pattern of loss associated with potential mechanisms of loss (non-disjunction, homologous sequence directed repair, or non-homologous sequence directed repair) following double stranded chromosome breaks and repair pathway dysfunction. By mapping sites of LOH (SSLP and haplotype markers) and correlating with gene expression profiles (cDNA and protein microarrays), and gene dosage imbalance (array CGH) we can determine the specific and determinant genetic events (quantitative trait loci). This approach will also identify genes that modify the induction and development of HSC neoplasms in susceptible and resistant mouse strains for extrapolation to human haplotypes and genotypes.